close

Вход

Забыли?

вход по аккаунту

?

Synthesis and Pharmacological Studies of Some 14-Naphthoquinono[32-c]-1H-pyrazoles2-Substituted Amino-14-naphthoquinones and Related Compounds.

код для вставкиСкачать
383
(1,4)-Naphthoquinono[3,2-c]-1H-pyrazoles
Synthesis and Pharmacological Studies of Some
(1,4)-Naphthoquinono[3,2-c]-1H-pyrazoles,
2-Substituted
Amino-1,4-naphthoquinones,and Related Compounds
V.K. Tandon', Meenu Vaish, J.M. Khanna', and Nitya Anand*
Department of Chemistry,Lucknow University, Lucknow-226007, India
Ranbaxy LaboratoriesLimited, New Delhi, India
tt
Central Drug Research Institute, Lucknow, India
+
Received May 26,1989
Series of (1.4)-Naphthoquinono(3,2-c>lH-pyrazolesand 2-substituted amino-1.4-naphthoquinones have been synthesised and studied for their possible
anticancer activity (animal tumours, Wulker 256 carcinosarmma). MluenZa
RNA tmnscriptase activity, ,antibiotic activity (C. neoformans,T.mentagraphytes. M . canis,A. niger, and C. albicans).
Synthese und pharmakologische Priifung einiger (Ip)-Naphthochinon[3&c]-lH-pyrazqle, Zsubstituierter Amino-l&naphthochinone und
verwandte Verbindungen
An o-aminoquinonoid unit is found in a number of antitumour antibiotics, e.g. streptonigrin, actinomycin, mitomycins, etc. To incorporate an o-aminoquinonoid unit and in
view of some salient structural features of Arnebins'**),the
synthesis of compounds 2,3,and 4 have been carried out to
study their anticancer activity against C . neoformans, T.
mentagraphytes, M . canis,A. niger, and C . albicans.
procedures, on condensation with secondary amines in
EtOH gave 2-substituted amino- 1,4naphthoquinones 3,
whereas with diazomethane and diazoacetic ester, it formed
compounds 2. Compound 1 (X=X'=H R=H) on refluxing
with 2-methylindole in EtOH gave compound 4.
Chemistry
Melting points: Townson and Mercer apparatus. - IR-spectra: PerkinElmer Model 137. - 'H-NhIR-spectra: Varian A-60 D,TMS BS internal
standard, 6 (ppm), J in HL - TLC: silica gel G or basic A1203 plates. Temp. in 'C.
The synthetic route to the title compounds is shown in
Scheme 1. Thus Naphthoquinones 1, prepared by known
1,4-Naphthochinon[3,2-~]-1H-pyrazoleand 2-substituierte Arnino-1,4naphthochinone wurden hergestellt und auf cytostatische Wirkung (Tiertumore,Wulker 256 Sarkom)), Influenza RNS-Transkriptase Aktiviat und antibiotische Wuksamkeit (C. neoformans, T. mentagraphytes, M . canis, A.
niger und C. albicans) gepriift.
Experimental Part
Table I
Compound
No.
X
3a
OH
3b
OH
X'
OH
OH
R
H
H
N<
I-Pyrrolidino-
I-Piperidino-
Yield
M.P.
%
OC
Molecular
formula
39
>300
C14H13N04
C
64.4
C15HisN04
H
N
C
C13HllN04
N
C
C15Hl~N04
N
C
5.32
5.0
65.7
5.45
5.8
63.9
4.63
5.8
65.7
5.50
4.7
66.1
5.50
4.5
63.4
5.68
8.9
37
>320
Analysis
Found %
Calcd. %
H
3c
OH
OH
Me
1-Ethyleneimino-
50
>320
H
3d
OH
OH
Me
I-Pymlidino-
74
>320
H
N
3e
OH
OH
Me
I-Piperidino-
70
>320
C16H17N04
C
H
N
3f
OH
OH
Me
N4Methyl-NPiperazino-
53
>320
Ci6H1&04
c
H
N
Arch. Pharm. (Weinheim)323,383-385 (1990)
OVCH Verlagsgesellschaft mbH. D-6940 Weinheim, 1990
64.9
5.02
5.4
65.9
5.49
5.1
63.7
4.48
5.7
65.9
5.49
5.1
66.5
5.92
5.0
63.2
5.96
9.3
0365-6233/90/0707-0383$03.50 + .25/0
384
Tandon and coworkers
2
0-4' for 48 h; then the mixture was concentrated to about 20 ml. The
product which separated was crystallized from EtOH to give a light brown
solid, yield 1.5 g (50%). mp. 239-40'. - IR (KBr) cm-': 1636 (C=O); 1723
(-CO-OEt); 3248 (-OH). - C14Hl$J206 (302.2) Calcd. C 56.3 H 3.31 N 9.3
Found C 56.0 H 3.80 N 9.2.
R=V
3
H N y
1 -Pyrrolidino-5.8-dihydroxy-l,4-naphihoquinone(3,
X=X' =OH;
R=N-pyrrolidino)
6
x'
Pyrrolidine (0.71 g, 0.01 mole) was added to naphthazarin (0.47 g.
0.0025 mole) in absol. EtOH (40ml). The mixture was kept for 72 h at
room temp. The solid product which separated was crystallized from absol.
EtOH, yield = 39%, mp. > 3 W . - IR (KBr) cm.': 1640(C=O); 3400 (-OH).
- CL4H13N04(259.2) Calcd. C 64.9 H 5.02 N 5.4 Found C 64.4 H 5.32 N
4.9.
Similarly, compounds 3a-f were prepared, their characterization data are
recorded in Table 1.
R
0
1
2-(2-Meihyl-3-indolyI)-I,4-naphihoquinone (4)
(a)
X = X' = H
(b) X = X' = OH
R = H, Me
R'
= H, COOEt
H3C
I
I /
4
A solution of 1.4-naphthoquinone (1.58 g, 0.01 mole) and 2-methylindole (1.31 g, 0.01 mole) in EtOH (50 ml) was refluxed for 6 hand left for 3
days at room temp. The dark violet coloured solid which separated was
crystallized from EtOH, yield 0.96 g (30%). mp. 174-76' (lit.? mp. 1768'). - IR (KBr) cm-': 3323 (-NH); 1657 (C=O). - CI9H13NO2(287.3) Calcd
C79.4H4.52 N4.9 FoundC 79.3 H4.68 N4.4.
Scheme 1
Pharmacology
5-Hydroxy-8-chloro-l,4-naphihoquinone
(8-Chlorojuglone)(1, X=OH,
X=CI, R=H)
Aniicancer-Screening
A mixture of p-chlorophenol (8.40 g; 0.66 mole) and maleic anhydride
(16.16 g, 1.70 mole) was added to a melt of anhydrous AICl3 (160 g) and
NaCl (32 g) kept at 180' with vigorous stirring. After the addition, the
temp. was raised to 200' for 5 min, cooled to 120' and the mixture was
poured onto HCI-ice. After standing for a few h, the product was filtered,
washed with HzO, dried and extracted with petroleum ether in a Soxhlet
apparatus, when 1 (X=OH, X'=CI, R=H) was obtained as petroleum ether
soluble fraction, yield 3.3 g (24%). mp. 201' (lit.3): 201-2'). - IR (KBr)
cm-': 1650 (H-bonded-C=O); 1670 (-C=O). 'H-NMR (CDCI3): 7.01 (s,
H-2, H-3), 7.28 (d, J = 8.5 Hz, H-6), 7.71 (d, J = 8.5 Hz, H-7).
-
5,8-Dihydroxy-l,4-naphihoquinone
(naphihazarin) (1, X = X =OH. R=H)
It was prepared in a similar manner, yield 27%. mp. 275-78' (lit.?
276-80'). - IR (KBr) cm-': 1610 (H-bond-C=O). - 'H-NMR (CDC13): 7.18
(s, H-2, H-3, H-6, H-7). 12.4 (broad, SOH, 8-OH, exchangeable with
D2O).
2-Meihyl-S,8-dihydroxy-l.4-naphihoquinone
(1, X = X =OH.R=Me)
It was prepared by a similar procedure, yield 30%. mp. 175-6' (lit?): mp.
173').
(I,4)-Naphihoquinono[3,2-c]-I
H-pyrazole(2,X = X =R' =H)
Diazomethane in ether (30 ml) was added to a solution of 1.4-naphthoquinone (1.58 g, 0.01 mole) in ether (100 ml) under ice cooling when a
yellow crystalline product separated after a few min, which was filtered
and crystallized from acetic acid; yield 1.78 g (89%), mp. 356' (lit!):
mp.
349').
3-Carbethoxy-5,8-dihydroxy-(l,4)-naphihoquinono[3,2-c]-1
H-pyrazole
( 2 ,X = X = O H , R'=COOEi)
Ethyl diazoacetate (1.14 g, 0.01 mole) was added to a solution of naphthazarin (1.90 g, 0.01 mole) in ether (200 ml) and allowed to stand between
The compounds were treated against animal turnours (Walker 256 Carcinosarcoma) following the standard procedure=). The tumour was implanted in the right thigh muscle of the rat with Walker 256 Carcinosarcoma cells. The treatment was given from 3rd to 6th day of tumour implantation intraperitoneally. On the 7th day, both hind legs of the rats were
removed from the hip joint and weighed. By substracting the weight of the
normal left leg from the tumour bearing right leg, the weight of the net
tumour was obtained.
Screening against nucleic acid polymerising enzymes - Reverse
transcripiase Inhibiiion (RNA-dependeniDNA polymerase)-
In this test, virion contained RNA dependent DNA polymerase from
Rauscher murine leukemia virus was activated and assayed by the method
of Baliimore and Smoller8).
Influenza RNA iranscripiase
The inhibition against influenza enzyme was measured by following the
method of Compans and Caliguiri').
Aniibioiic Screening:
The compounds were tested for their antibiotic activity by standard
methods'").
Results and Discussions
Anticancer Activity
The tumour weight of the treated group was devided by
the tumour weight of the control group, the ratio is expressed as T/C. For synthetic compounds a T/C % index of
42 or less is considered indicative of drug activity. The
results are summarised in Table 2.
Arch. Pharm. (Weinheim) 323,383-385 (1990)
385
( 1.4)-Naphthquinono[3,2-c]-1H-pyrazoles
Table 2
Compound
Naphthazarin
2-Methylnaphthazarin
5-Amino- 1.4-naphthoquinone
2-Methyl-3-( 1-piperidino)-naphthaarin
(1,4)-~aphthquinono-(3.2-C)-1H-Pyrazole
2-(2-Methyl-3-indoIyl)- 1.4-naphthoquinone
Dose
mgncg
Survivors
TIC %
Remarks
10
2.5
2.5
50
50
50
314
414
414
313
313
3t3
37
23
112
107
115
87
active
active
inactive
inactive
inactive
inactive
Table 3
Compound
Control
8-Chloro-5-hydroxy- 1,
4-naphthoquinone
Table 4
DPM
% Control
340 f 25
373 f I5
25
55
1. Naphthazarin and 2-methyl naphthazarin were found to
be active against Walker 256 carcinosarcoma.
2. In tissue culture (KB system), 5-hydroxy-8-chloro- 1,4naphthoquinone showed anticancer activity though at a high
dosage, -0.95 ED50 2.1 x 10.
Activity against nucleic acid polymerising enzymes
Some compounds have been tested involving nucleic acid
polymerising enzymes: WSN influenza, poliovirus induced
RNA-dependent RNA polymerase, infleunza RNA transcriptase, and RNA-dependent DNA polymerase.
Reverse Transcriptase inhibition (RNA-dependent DNA
Polymerase)
8-Chloro juglone showed 97% activity at concentration of
56 pM.Other compounds did not show any significant activity.
RNA- Dependent RNA polymerase activity
This enzyme is induced in poliovirus type 2 infected Hela
cells. The activity peaks 6 h after injection and is found
associated with the membranes. The cells are disrupted at
this stage by gentle homogenisation after hypotonic swelling and the membranes are differentially centrifuged from
debris and nuclei. The assay measures 3H-uridine triphosphate incorporation. The results are summarised in Table 3.
None of the other compounds tested showed any inhibition
against WSN influenza virus on MDBK cells.
Influenza RNA transcriptase Activity
No inhibition by these compounds was found against intact influenza or polio system. The results against influenza
enzyme are given in Table 4.
Arch. Pharm. (Weinheim)323.383-385 (1990)
Compound
% Inhibition at
10 pg/ml
Naphthazarin
2 4 1-Ethyleneimino)-3-methyl-5,8dihydroxy- 1,4-naphthoquinone
129
120
2-Pyrrolidino-3-methyhyl-5,8-dihydroxy1,4-
107
naphthoquinone
Table 5
Compound
2-(2-methyl)-3indolyl- 1.4naphthoauinone
C. neoformans
T. meniagraphytes
M. canis
12.5
25.0
12.5
A. niger
C. albicam
25.0
Antibiotic Activity
The compounds were tested for their antibiotic activity by
standard methods") and those showing activity are listed in
Table 5.
Thus, these compounds do show weak to strong inhibition
of different biological systems.
References
a) Y.N. Sukla, J.S. Tandon, D.S. Bhakuni, and M.M. Dhar, Experientia
25,357 (1969).
b) Y.N. Sukla, J.S. Tandon, D.S. Bhakuni, and M.M. Dhar, Phytochemistry 10,1909 (1971).
2 a) S.K.Guptaand I.S. Mathur, Ind. J. Cancer 9,50(1972); C.A. 77.69
(1972).
b) Y.N. Sukla, J.S. Tandon, and M.M. Dhar, Ind. J. Chem. 11, 528
(1973): C.A. 79,337 (1973).
3 R.G. Cooke, H. Dowd, and W. Segal, Australian J. Chem. 6 . 38
(1953).
4 K. Zahn and P. Ochwat. Reagents for Organic Synthesis, Fieser &
Fieser, p. 1027, John Wiley and Sons, Inc., N.Y. 1967.
5 A. Killen Macbeth, J.R. Price. and F.L. Winzor, J. Chem. SOC.325
(1935).
6 L.F. Fieser and Mary A. Peters, J. Am. Chem. SOC.53,4080 (1931).
7 J.D. Bu'Lock and J. Harley-Mason, J. Chem. SOC.703 (1951).
8 D. Baltimore and D. Smoller, Proc. Nat. Acad. Sc., U.S.. 68. 1507
( 1971).
9 R.W. Compans and L.A. Caliguiri, Virology 11,441 (1973); C.A. 78,
222 (1973).
10 M.L. Dhar, M.M. Dhar, B.N. Dhawan, B.N. Mehrotra, and C. Ray,
Ind. J. Exptl. Biol. 6,232 (1968).
[Ph7021
1
Документ
Категория
Без категории
Просмотров
0
Размер файла
227 Кб
Теги
synthesis, pyrazole, compounds, amin, naphthoquinone, related, substituted, studies, pharmacological
1/--страниц
Пожаловаться на содержимое документа